“Why am I still suffering?”: Experience of long-term fatigue and neurocognitive changes in oropharyngeal cancer survivors following (chemo)radiotherapy

Highlights • Limited data exist on survivorship after oropharyngeal cancer with existing literature focused predominantly on head and neck–specific physical functional deficits.• This study examines the lived experience of fatigue and neurocognitive deficits in survivors of oropharyngeal squamous cell cancer and impact on their daily lives.• Cognitive fatigue and neurocognitive impairment across several domains were frequently experienced by survivors of oropharyngeal cancer (at least two years post-treatment) affecting quality of life.• Survivors felt ill-prepared for these late sequelae, highlighting opportunities for the improvement of patient information and support services.


Introduction
Head and neck cancers (HNC) represent a heterogenous group of diseases and account for more than 660,000 new cases annually [1,2].Carcinogenic human papilloma virus (HPV) has resulted in an increased incidence of oropharyngeal cancer (OPC) with most cases observed in patients < 65 years of age and associated with a more favourable prognosis [3][4][5][6][7].Treatment is generally multimodal, with concurrent chemoradiotherapy (CRT) being standard of care [2,8].Late effects of CRT are a key survivorship issue.These include permanent loss of saliva, swallow dysfunction, dysgeusia, lymphoedema, skin fibrosis, and neuropathy amongst other toxicities [9][10][11].Consequently, patients treated for OPC, can face years of survival with significantly impaired quality of life(QoL)due to late effects of curative treatment [12].
The National Comprehensive Cancer Network (NCCN) defines fatigue as "a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning" [13].It is one of the most prevalent and distressing late effects of cancer treatment [14,15].Chronic fatigue (CF) is fatigue lasting for six months or more [16,17].In a cross-sectional study of patients with HNC, a moderate-to-severe fatigue rate of 18 % at least 1 year after RT was reported [18].This is high in comparison to a prevalence rate in the general population of approximately 0.5-1 % [19,20].Fatigue appears to remain an issue throughout survivorship, with a prospective longitudinal study in HNC survivors showing ongoing fatigue from 1 to 5 years of follow-up, without demonstration of recovery [21].
During head and neck radiotherapy (RT) normal brain tissues may receive a low radiation dose, and this could have a detrimental effect on neurocognitive function [22][23][24].Several small retrospective HNC series report neurocognitive dysfunction within 2 years of treatment [25][26][27].
Observed cognitive decline appears to persist > 5 years post-treatment [28][29][30] and memory problems, fatigue, anxiety and reduced QoL are reported in HNC survivors [29][30][31][32][33][34][35][36].These studies are limited by small sample sizes, heterogeneity of HNC patients sampled or a sole focus on nasopharyngeal cancer.Furthermore, neurocognition was often assessed using screening tools which lack sensitivity and domainspecific information.In addition, previous studies have mostly had quantitative methodology [36], which although valuable, lacks contextual information on how late effects may impact on patients' everyday lives.
To obtain greater insight into patient quality of life, ROC-oN (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition reference 22/WM/0207), a mixed method cross sectional study evaluating fatigue and neurocognitive function in patients following RT +/-chemotherapy for OPC and impact on QoL was carried out.Here, we report on the qualitative arm of ROC-oN performed to gain a better understanding of survivors' perspectives and experiences.

Study design
This qualitative investigation is part of a larger multicentre study, approved by the West Midlands Research Ethics Committee in October 2022 (22/WM/0207).The full study involved patients with OPC being invited to complete a quantitative survey and an online unsupervised cognitive test battery, after which a subset of participants were invited for qualitative interviews.Here, we report on the qualitative findings only.We used semi-structured interviews and thematic analysis, supported by a reflexive approach [37][38][39].

Setting and participants
Patients treated for OPC with primary RT (+/-chemotherapy) in Leeds Cancer Centre or The Christie NHS Foundation Trust from 2010 to 2020, with ≥ 24 months follow-up and disease free at time of recruitment, were identified from existing institutional databases and sent postal invitations.Exclusion criteria were inability to consent, limited English language proficiency, surgery prior or after RT.
Following completion of quantitative data collection, participants indicated their willingness to be contacted for interview.To strike a balance between meaningful representation and resource constraints, approximately 10 % of the total eligible study participants were approached.Convenience and purposive sampling techniques were adopted to obtain a varied participant sample by age (at treatment and time of study), tumour subsite (e.g., tonsil, base of tongue), Tumour-Node-Metastasis (TNM) staging, HPV status, time interval since end of treatment, level of education and employment status.
Interviews were conducted March to June 2023.Verbal and written study information was provided and written or recorded verbal consent was obtained.

Data collection
Interviews were conducted by telephone or online video platform, dependent on participant preference.Interviews were semi-structured, exploring fatigue and neurocognition since treatment and other late effects.
Neurocognitive deficits referred to impaired ability to pay attention, concentrate, remember, follow conversations, multitask and/or a general sense of limitations in linguistic and arithmetic capabilities [40].The NCCN definition of fatigue was adopted [13].As both are multidimensional constructs, there is some overlap between the emotional and cognitive aspects of fatigue and neurocognitive function, and fatigue will impact on neurocognitive performance.For the purpose of this study, emotional/cognitive fatigue was considered a psychobiological state caused by demanding neurocognitive tasks, presenting as a feeling of tiredness, lack of energy, decreased motivation and alertness [41,42], while physical fatigue referred to the physical sensation of tiredness and impact of fatigue on physical activity [13,43].
Interviews were conducted with participants one-to-one by one of two researchers with different backgrounds (ZIE a clinician and EN a sociologist and experienced qualitative researcher).An interview guide (supplementary information 1) was used.Reflective notes were made after interviews and regular discussions held within the research team.

Analysis
Data collection was completed when theoretical saturation was achieved and sufficient depth of understanding attained in order to address the research questions [44].Interviews were transcribed verbatim and analysed using reflexive thematic analysis [37,38] taking into account our role as researchers in the study.The study employed a paradigmatic framework of interpretivism and constructivism.We aimed to explore patients subjective experience of fatigue and neurocognitive abilities after OPC treatment, whilst acknowledging the importance of researcher influence in such interpretations.No specialised qualitative software was used.
All transcripts were read and then coded (ZIE), with coding being inductive to fully understand participant experiences but also deductive to find data to address the research objectives.Initial codes were subsequently categorised into potential sub-themes and themes (coding summary table in supplementary information 2) and coding regularly discussed with research team (EN, FB, LM).
A second coder (EN) was used to sense-check ideas and explore multiple assumptions or interpretations of the data [37][38][39], thereby developing richer interpretations of meaning, instead of striving to achieve consensus of meaning.

Results
A total of 257 ROC-oN study participants expressed an interest in being interviewed, of whom 33 were approached and 21 were interviewed (Table 1 shows participant characteristics).Interviews took on average 52 min (range 41-70).11 men and 10 women participated, median age was 58 years and median time post-treatment was 5 years (inter quartile range 4-8).All participants received CRT.Interviews produced six themes with sub-themes, as discussed below.
Unexpected burden of fatigue: "I did not expect to still feel quite so tired now at 2-3 years down the road" Participants all experienced fatigue during and/or in the weeks after RT.For most this was incapacitating and like no previous experience.Fatigue gradually improved 4-6 months post-treatment but for some, fatigue persisted for several years.In most participants with CF, it was mild to moderate, however, in a few cases fatigue was severe.Irrespective of the degree of CF, participants did not confuse this with normal tiredness and reported they never returned to baseline (Table 2, section A, Comment 2).
Whilst acute fatigue appeared present more in the physical domain, CF appeared most in the dimension of emotional/cognitive fatigue, often described as "brain fog" or being "fuzzy headed" (Table 2, A4 &5).One participant described being more physically active and going to the gym but being burdened by a lack of "emotional connection", leaving them unable to commit to work or pursue career progression.Other participants expressed difficulty in finding motivation to take on complex tasks at work, leading on workplace projects and struggling with working on a computer.
Participants with CF post-treatment were unsure what to attribute symptoms to.They felt fatigue could be due to aging, fluctuating hormone levels, or hypothyroidism.Participants thought getting older might have caused some decline in endurance and energy levels and female participants also mentioned normal physiological endocrine changes such as menopause could impact fatigue.Yet, participants were not convinced these factors fully explained their CF and questioned if it could be due to their OPC treatment (Table 2

, A6).
Noticing changes in neurocognitive performance: "Is it just me?Why am I doing this, what's going on here?"Some participants reported noticing unexplained changes in neurocognitive functioning after the first-year post-treatment which became more apparent in the longer term (Table 2, section B, comment 2).One participant reported experiencing neurocognitive deterioration within the first few weeks of treatment completion.
Amongst participants, change in neurocognitive performance was noticed across several domains.Memory was the most commonly and most severely affected domain.This was mild for most participants: they expressed they struggled to remember names of people, items in a food order or occasional appointments.However, for some, severe memory issues were described, e.g., being unable to remember people they had known for over a decade (Table 2, B5).Most participants expressed issues with 'short-term' memory; struggling to recall facts shortly after information had been received.
Attention, especially sustained attention, was another commonly affected domain, with participants struggling to concentrate on simple tasks such as responding to telephone messages, watching a film, or reading a book.Changes in processing speed were reported as well: taking onboard information, processing it, and reaching a decision was much slower than pre-treatment (Table 2, B8).Participants also reported impairment in planning skills when taking part in handiwork.
In one participant who reported no visual problems, impaired spatial awareness was suggested, with a lack of awareness for "danger or space" expressed.This led to an accident in which the participant sustained significant physical injury.It is possible that this could be linked to impaired memory of spatial information.

The new normal: "work has certainly changed, and I get kind of concerned"
Participants who returned to employment after treatment reported fatigue was exacerbated by the demands of work and neurocognitive changes made work challenging.For example, participants described not being able to go over work emails quickly, having to double check their work several times and struggling to deal with high level and load of information (Table 2, C4&6).This consequently often translated to a change in work pattern (going part-time) and, in some cases a change in job role (i.e., stepping down from managerial roles).For a few participants despite modifications to work pattern and job role, they described being to cope with the physical and psychological demands of work and were unable to retain employment (Table 2, C3).Some participants stated, re-learning relevant activities and skills fostered a feeling of competency despite impaired neurocognitive performance.
Participants said neurocognitive changes negatively influenced engagement with hobbies and interests (e.g., reading, handicrafts).Instrumental activities of daily life such as driving, which were effortless       pre-treatment, became difficult for some.Relationships with family and friends were reported to suffer strain in some cases, leading to social isolation (Table 2, C9).Participants also linked impairment in neurocognitive function and fatigue to low mood and anxiety.Sometimes this exacerbated anxiety around cancer recurrence.Inability to perform at a desired level led to frustration, however some participants maintained a positive attitude and persevered.Participants wanted to be aware and keep track of further neurocognitive changes.

Navigating changes: "I have learnt to manage what I have to do in my own way"
To manage memory issues, keeping notes, making lists and routines were the most favoured strategies reported by participants.These memory aids appeared sufficient for participants with mild memory loss.To self-manage cognitive fatigue and neurocognitive deficits, participants also expressed they had to take rests or move through the day at a slower pace.In addition, for some, dividing tasks to optimise participation in desired daily life activities and a different approach to organising tasks was required with more mentally taxing tasks done in the morning (tabl2 2, section D, comment 1-3).Some participants also highlighted adopting healthy eating habits as a strategy to manage fatigue.
Most participants with CF or neurocognitive changes described receiving support from work colleagues and that this was vital to remaining in employment.Many expressed increased reliance on family (Table 2, D8).Participants were grateful for their family's understanding and support, but also aware of some loss of independence and feeling like an additional burden on their family.Some participants expressed a positive outlook and this positive psychology had significant impact on how they managed late effects and promoted proactive measures to protect health.
Insufficient awareness: "Six years down the line, this is why I am thinking why am I still suffering?I wish they had told me it would be as longterm as it is" Participants experienced a wide range of physical late effects from treatment (supplementary Table 2), to varying degrees.These late effects presented difficult challenges to participants, e.g., impaired salivary gland function, problems with swallowing and oral pain served as a daily reminder of treatment, impacting physical nutritional needs, making eating an obligation and impacting negatively on social aspects of eating.
Many participants described being generally unprepared for the late consequences of treatment (Table 2, section E, comment 3).Fatigue was mentioned but not emphasised during the pre-treatment consent process, making it easy to underestimate its long-term impact.One participant recalled chemotherapy-related brain fog was mentioned but others had no recollection of long-term changes in neurocognition being mentioned as a potential late effect(Table 2 , E5).This meant many had to source information for themselves on the internet.
Participants said they would like to have been better informed and equipped to recognise the late effects they are at risk of developing (Table 2, E8&9).They expressed being more informed of CF and possible neurocognitive changes would validate their experience, allow better preparation, adoption of self-care behaviour, and ultimately help them cope more efficiently.Participants also felt being informed prior to treatment of such potential late effects prior would mean family/carers could identify, understand, discuss, and better support them if changes in neurocognitive abilities were to develop.
Required support: "just a waste of my time and their time, that's reality" The desire to seek support for late effects (supplementary information 3) was in some cases hindered by expectations participants felt they needed to meet.Some felt pressured to have moved on from their cancer diagnosis and be fully recovered from their treatment.Participants felt fatigue or neurocognitive changes were not priorities at follow-up visits with health professionals, with the focus being mostly on potential cancer recurrence and better known physical late effects such as dry mouth or swallowing problems.Participants expressed their impression of healthcare professionals having a poor understanding of, or interest in, fatigue and neurocognitive changes (Table 2, section F, comment 3).This made them feel doubtful healthcare professionals could help with these issues.In this respect, most participants did not feel the support offered during follow-up was adequate (Table 2, F4).Difficulties getting appointments (the further out from the treatment they were), and the quality of consultations were criticised.Some participants did find support groups valuable, allowing honest conversations and helping to validate their experiences and emotions, thus providing a feeling of reassurance.

Discussion
The experience of late effects following treatment for OPC is diverse and there is limited data on neurocognition and fatigue in an OPC-only cohort.This is the first study to qualitatively investigate OPC survivors' experiences of CF and self-perceived change in neurocognitive abilities.
Findings suggest OPC survivors experience fatigue which persists into long-term survivorship.Although the precise pathophysiology behind CF following cancer treatment remains unclear, inflammation, depression, impaired sleep, comorbid conditions, or other late effects are implicated as contributory factors [17,[45][46][47].Yet, similar to other cancer groups and in contrast to international guideline recommendations [48], OPC survivors' fatigue is not routinely assessed or managed in practice.
In this study, participants experienced severe physical fatigue in the immediate post RT period, with this subsiding as acute RT effects settled.Beyond this timeframe, emotional/cognitive fatigue emerged as the more affected domain in participants with CF.In a review which assessed the multiple-symptom concept of fatigue in a cancer cohort, physical fatigue was reported to increase during anti-cancer therapy, decreasing significantly afterwards [43].That said, the longitudinal course of emotional and cognitive fatigue is less certain, with contradictory findings reported [43].Emotional and cognitive fatigue in participants usually presented with difficulty concentrating.Similar to patients with chronic fatigue syndrome [49], emotional and cognitive fatigue could be an important correlate of cognitive impairment in OPC survivors, corroborating the multifactorial and multidimensional nature of these constructs, with overlapping elements.
Participants self-reported neurocognitive complaints several years post-treatment.Several domains of functioning were affected in our sample: attention/concentration, processing speed and especially memory.Subjective assessment of short-term memory by participants was in keeping with impairment in working memory.Working memory, which has been widely studied, refers to short-term maintenance of information in the absence of sensory input, and plays a vital role in guiding complex cognitive behaviour [50].A previous study attributed perceived neurocognitive functioning as an important predictor of communicative outcomes in HNC survivors [32].The current finding expands further on how attention, memory, and problem-solving affect functioning across several aspects of daily life, including limiting the capacity to return to work following non-surgical treatment.A Finnish study of a heterogenous group of cancer survivors (not including HNC), found 19 % reported deterioration in mental work ability [51].Paid work is known to boost an individual's financial, social and psychological health [52] and is an important component of QoL [53].In this study, support from employers played a vital role in being able to return to work successfully and retain employment in the same job role as pretreatment.Our data also showed neurocognitive impairment threatened social participation, leisure activities, emotional equilibrium and mood.
Compensatory strategies were self-developed by participants and applied to everyday life.These included memory aids, adopting a slower pace for demanding tasks and relearning, which are integrated coping mechanisms.Retraining, which is the repeated practice of tasks, and compensation, which is focusing on learning new strategies and alternative means to improve daily functioning, form an integral part of cognitive rehabilitation programmes [54].This has been used successfully to improve neurocognitive outcomes in stroke, traumatic brain injury and brain tumour patients [55][56][57][58].Participants also relied on physical and psychological support from carers.However, they reported being reluctant to seek assistance to avoid burdening caregivers.Current late effect follow-up services were reported as providing inadequate support for neurocognitive problems and fatigue.
Similar to other studies in cancer patients, there is a perceived lack of adequate information exchange, with improved pre-treatment counselling and information dissemination regarding chronic fatigue and the possibility of neurocognitive impairment being required [59][60][61].For many participants, their experiences differed significantly from their expectations.In an online survey of 403 US patients treated with RT the greatest divergence between pre-treatment expectations and toxicity from cancer treatment related to energy levels, particularly following multimodality therapy [59].Increased awareness of neurocognitive dysfunction and fatigue, could aid the emotional adjustment of survivors living with these issues and help families understand limitations in what survivors can and cannot do as well as before [62].
This study has limitations.First, all participants received CRT and our findings may not reflect the experiences of patients treated with RT alone.However, it is important to recognise qualitative studies do not aim to produce generalisable findings.Second, we asked long-term survivors to reflect on their whole cancer trajectory, hence there may be some recall bias.This investigation is also limited to patient perspectives only.
Despite these limitations, this study has several strengths.We focused on an OPC-only cohort, which is under-researched.Qualitative methodology allowed us to explore in-depth, the experience and impact of fatigue and neurocognitive changes.It highlights the impact of these changes on personal health, relationships, work, sense of security and social belonging.
Results of this study could enhance patient understanding and increase clinician awareness of the potential risks of post-radiotherapy neurocognitive issues and fatigue.Going forward these risks should be integrated into informed treatment decision-making.Neurocognitive and fatigue assessments should ideally be incorporated into routine follow-up protocols to allow timely intervention, if required.Future research could evaluate the impact of coping strategies, long-term support programs and interventions for managing or mitigating these issues, all with the ultimate goal of optimising quality of life in OPCSs.

Conclusion
This study provides valuable insight into survivors' experience of fatigue and neurocognitive changes following RT for OPC.Emotional and cognitive fatigue were most affected, along with cognitive complaints across several domains, with a likely strong correlation between these late effects.Increased awareness of neurocognitive impairment and fatigue as survivorship issues is required.Recognition of these longterm effects has the potential to improve support services and QoL.

Statements and declaration
The authors declare that they have no known competing relevant financial or non-financial competing interests to report

Table 2
(continued ) "I had no idea the impact long-term.you've got no idea what's coming really, …… I could have never in my wildest dream[imagine], the impact it has on (continued on next page) Z. Iyizoba-Ebozue et al.